EP2007717A1 - Nouveaux composés sulfonamides - Google Patents

Nouveaux composés sulfonamides

Info

Publication number
EP2007717A1
EP2007717A1 EP07735447A EP07735447A EP2007717A1 EP 2007717 A1 EP2007717 A1 EP 2007717A1 EP 07735447 A EP07735447 A EP 07735447A EP 07735447 A EP07735447 A EP 07735447A EP 2007717 A1 EP2007717 A1 EP 2007717A1
Authority
EP
European Patent Office
Prior art keywords
dimethoxy
amino
benzenesulfonyl
chloro
ylmethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07735447A
Other languages
German (de)
English (en)
Inventor
Hamed Aissaoui
Christoph Boss
Markus Gude
Ralf Koberstein
Thierry Sifferlen
Cornelia Zumbrunn Acklin
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Actelion Pharmaceuticals Ltd
Original Assignee
Actelion Pharmaceuticals Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Actelion Pharmaceuticals Ltd filed Critical Actelion Pharmaceuticals Ltd
Publication of EP2007717A1 publication Critical patent/EP2007717A1/fr
Withdrawn legal-status Critical Current

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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the present invention relates to novel sulfonamide compounds of formula (I) and their use as pharmaceuticals.
  • the invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of formula (I), and especially their use as orexin receptor antagonists.
  • Orexins are novel neuropeptides found in 1998 by two research groups, orexin A is a 33 amino acid peptide and orexin B is a 28 amino acid peptide (Sakurai T. et al., Cell, 1998, 92, 573-585).
  • Orexins are produced in discrete neurons of the lateral hypothalamus and bind to the G-protein-coupled receptors (OXi and OX 2 receptors).
  • the orexin- 1 receptor (OXi) is selective for OX-A
  • the orexin-2 receptor (OX 2 ) is capable to bind OX-A as well as OX-B.
  • Orexins are found to stimulate food consumption in rats suggesting a physiological role for these peptides as mediators in the central feedback mechanism that regulates feeding behaviour (Sakurai T. et al., Cell, 1998, 92, 573-585).
  • Orexin receptors are found in the mammalian brain and may have numerous implications in pathologies such as dysthymic, mood, psychotic and anxiety disorders; diabetes and appetite, taste, eating, or drinking disorders; hypothalamic diseases; disturbed biological and circadian rhythms; sleep disturbances associated with diseases such as neurological disorders, neuropathic pain and restless leg syndrome; insomnias related to psychiatric disorders; sleep apnea; narcolepsy; idiopathic insomnias; parasomnias; benign prostatic hypertrophy; all dementias and cognitive dysfunctions in the healthy population and in psychiatric and neurologic disorders; and other diseases related to general orexin system dysfunctions.
  • pathologies such as dysthymic, mood, psychotic and anxiety disorders; diabetes and appetite, taste, eating, or drinking disorders; hypothalamic diseases; disturbed biological and circadian rhythms; sleep disturbances associated with diseases such as neurological disorders, neuropathic pain and restless leg syndrome; insomnias related to psychiatric disorders; sleep apne
  • N-glycinsulfonamide derivatives which are non-peptide antagonists of human orexin receptors. These compounds are in particular of potential use in the treatment of e.g. eating disorders, drinking disorders, sleep disorders, or cognitive dysfunctions in psychiatric and neurologic disorders.
  • WO 00/50391 discloses certain sulfonamide derivatives as modulators of the production of amyloid ⁇ -protein.
  • WO 02/32864 discloses certain sulfanilide derivatives useful in the treatment of diseases mediated by oxytocin and/ or vasopressin.
  • 3418 discloses sulfonylamino-acetic acid derivatives as selective OX 2 receptor antagonists. Recently sulfonamide derivatives as selective OX 2 receptor antagonists have been described in WO 2006/024779.
  • a first aspect of the invention consists of a compound of the formula (I)
  • A represents
  • B represents O or S
  • V represents -O-, -S-, -N(R 2 )- or -C(H)(R 2 )-;
  • W represents -C(H)(R 2 )-;
  • Z represents -O-, -S-, -N(R 2 )-, or -C(H)(R 2 )-;
  • R 1 represents halogen or cyano
  • R 2 represents hydrogen or (Ci_ 4 )alkyl
  • R represents (Ci_ 4 )alkyl, (C 3 _ 6 )cycloalkyl or hydroxy(Ci_ 4 )alkyl;
  • R 4 represents (Ci_4)alkyl or an unsubstituted or mono or di-substituted five or six-membered heteroaryl wherein the substituents are independently selected from the group consisting of halogen, (Ci_4)alkyl, (Ci_4)alkoxy, trifluoromethyl, difluoromethoxy and trifluoromethoxy;
  • R 5 represents N(CH 3 ) 2 , or isopropenyl.
  • (Ci_ 4 )alkyl means a straight-chain or branched-chain alkyl group with 1 to 4 carbon atoms.
  • Examples of (Ci_ 4 )alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec. -butyl or tert.-butyl. Preferred are methyl and ethyl.
  • presents "(Ci_ 4 )alkyl” the term means methyl and ethyl, preferably methyl.
  • R 3 represents "(Ci_4)alkyl” the term means methyl and ethyl, preferably ethyl.
  • R 4 represents “(Ci_ 4 )alkyl” the term means methyl and ethyl, preferably methyl.
  • the term "hydroxy(Ci_ 4 )alkyl”, alone or in combination, means a group of the formula HO- (Ci_ 4 )alkyl-, in which the term "(Ci_ 4 )alkyl” has the previously given significance, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy or tert.-butoxy.
  • (Ci_4)alkoxy means a group of the formula (Ci_4)alkyl-0- in which the term "(Ci_4)alkyl” has the previously given significance, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy or tert.-butoxy.
  • methoxy and ethoxy are preferred methoxy.
  • (C 3 _ 6 )cycloalkyl means a cycloalkyl ring with 3 to 6 carbon atoms.
  • Examples of (C 3 _ 6 )cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Preferred is cyclopropyl.
  • heteroaryl alone or in combination, means a 5- to 10-membered monocyclic or bicyclic aromatic ring containing for example 1 , 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur which may be the same or different. Preferred are monocyclic aromatic rings.
  • heteroaryl groups are furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl or phthalazinyl,
  • Preferred heteroaryl groups are: oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, pyridyl, pyrimidyl or pyrazinyl.
  • the heteroaryl group may be unsubstituted.
  • the heteroaryl group may also be independently mono- or disubstituted wherein the substituents are independently selected from the group consisting of halogen, (Ci_ 4 )alkyl, (Ci_ 4 )alkoxy, trifluoromethyl, difluoromethoxy and trifluoromethoxy.
  • Preferred substituents are: halogen, (Ci_4)alkyl, (Ci_4)alkoxy and trifluoromethyl (more preferred: chlorine, methyl, methoxy and trifluoromethyl).
  • Preferred is a five or six-membered heteroaryl.
  • Preferred heteroaryl groups are:
  • N' or «f(R 2 )-", alone or in combination, means "-N(H)-” or "-N((C 1-4 )alkyl)-" wherein the term (Ci_4)alkyl has the above meaning.
  • Preferred example is -N(CHs)-.
  • the term "-C(H)(R 2 )-", alone or in combination, means "-C(H)(H)-” or "-C(H)(Ci_ 4 )alkyl)-" wherein the term (Ci_ 4 )alkyl has the above meaning.
  • Preferred example is -C(H)(CH 3 )-.
  • any reference to a compound of formula (I) is to be understood as referring also to enantiomers, mixtures of enantiomers such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, and mixtures of diastereomeric racemates, as well as salts (especially pharmaceutically acceptable salts) and solvates (including hydrates) of such compounds, and morphological forms, as appropriate and expedient.
  • salts encompasses either salts with inorganic acids or organic acids like hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, phosphorous acid, nitrous acid, citric acid, formic acid, acetic acid, oxalic acid, maleic acid, lactic acid, tartaric acid, fumaric acid, benzoic acid, mandelic acid, cinnamic acid, pamoic acid, stearic acid, glutamic acid, aspartic acid, methanesulfonic acid, ethanesulfonic acid, ethanedisulfonic acid, p-toluenesulfonic acid, salicylic acid, succinic acid, trifluoroacetic acid, and the like that are non toxic to living organisms or, in case the compound of formula (I) is acidic in nature, with an inorganic base like an alkali or earth alkali
  • salts such as sodium hydroxide, potassium hydroxide, calcium hydroxide and the like.
  • compounds having acidic groups such as a carboxy group or a phenolic hydroxy group, may form metal or ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or suitable organic amines, such as tertiary monoamines, for example triethylamine roxyethyl)-amine, or heterocyclic bases, for example JV-ethyl-piperidine or N,N'- dimethylpiperazine. Mixtures of salts are possible.
  • Salt-forming groups are groups or radicals having basic or acidic properties.
  • Compounds having at least one basic group or at least one basic radical, for example amino, a secondary amino group not forming a peptide bond or a pyridyl radical, may form acid addition salts, for example with inorganic acids.
  • acid addition salts for example with inorganic acids.
  • mono- or poly-acid addition salts may be formed.
  • a further embodiment of the invention comprises compounds of formula (I), wherein B represents O.
  • a further embodiment of the invention comprises compounds of formula (I), wherein Z represents -S-.
  • a further embodiment of the invention comprises compounds of formula (I), wherein R 2 represents methyl.
  • a further embodiment of the invention comprises compounds of formula (I), wherein R 1 represents chlorine.
  • a further embodiment of the invention comprises compounds of formula (I), wherein R 3 represents (Ci_ 4 )alkyl, (C 3 _ 6 )cycloalkyl or hydroxy(Ci_ 4 )alkyl.
  • a further embodiment of the invention comprises compounds of formula (I), wherein R 4 represents an unsubstituted or mono or di-substituted five or six-membered heteroaryl, substituted with halogen, (Ci_4)alkyl, (Ci_4)alkoxy, trifluoromethyl, difluoromethoxy, or trifluoromethoxy.
  • a further embodiment of the invention comprises compounds of formula (I), wherein R 5 represents N(CHs) 2 .
  • bodiment of the invention comprises compounds of formula (I), wherein A represents:
  • a further embodiment of the invention comprises compounds of formula (I), wherein the compounds are selected from
  • Compounds as described above have IC 50 values below 50 nM at least on one of the orexin receptor, which have been determined with the FLIPR (Fluorometric Imaging Plates Reader) method described in the experimental section. Preferred compounds are active against both, OX 2 receptors. Particularly preferred compounds have IC 50 values below 20 nM on OXi and OX 2 receptors.
  • the compounds according to formula (I) are useful in the preparation of a medicament for the prevention or treatment of diseases selected from the group consisting of sleep disorders including insomnias; parasomnias; disturbed biological and circadian rhythms; narcolepsy; sleep disturbances associated with neurological disturbances such as neuropathic pain and restless leg syndrome; obstructive and non obstructive sleep apnea; idiopathic insomnias; insomnias related to psychiatric disorders including dysthymic, mood, psychotic and anxiety disorders; addictions; generalized anxiety, all types of phobias, obsessive compulsive disorder, panic anxiety, post-traumatic stress disorders; affective neurosis; depressive neurosis; anxiety neurosis; schizophrenia and psychosis; attention deficit and hyperactivity disorder; manic depression; delirium; all types of addictions to psychoactive substances or natural reward; sexual dysfunction; psychosexual dysfunction; pathological gambling; tolerance and dependence to narcotics or withdrawal from narcotics; dissociative disorders; adjustement and personality
  • Compounds of formula (I) are particularly suitable for use in the treatment of diseases or disorders selected from the group consisting of eating and/or drinking disorders, all types of sleep disorders,all kinds of cognitive dysfunctions in the healthy population and in psychiatric and neurologic disorders.
  • Eating disorders comprise metabolic dysfunction; dysregulated appetite control; compulsive obesities; emeto-bulimia or anorexia nervosa.
  • Pathologically modified food intake may result from disturbed appetite (attraction or aversion for food); altered energy balance (intake vs.
  • Drinking disorders include polydipsias in psychiatric disorders and all other types of excessive fluid intake, including alcohol.
  • Sleep disorders include all types of insomnias, narcolepsy and other disorders of excessive sleepiness, sleep-related dystonias; restless leg syndrome; sleep apneas; jet-lag syndrome; shift-work syndrome, delayed or advanced sleep phase syndrome or insomnias related to psychiatric disorders.
  • Insomnias are defined as comprising sleep disorders associated with aging; intermittent treatment of chronic insomnia; situational transient insomnia (new environment, noise) or short-term insomnia due to stress, grief, pain or illness.
  • Cognitive dysfunctions include deficits in all types of attention, learning and memory functions, at all stages of memory formation and consolidation occurring transiently or chronically in the normal, healthy, young, adult or aging population, and also occurring transiently or chronically in psychiatric, neurologic, cardiovascular and immune disorders.
  • Indications include learning disabilities and memory impairment due to toxicant exposure, brain injury, age, neurodegeneration, autoimmunity, schizophrenia, anxiety, depression, epilepsy, mental retardation in children, Down's Syndrome and senile dementia, including disease, anterior Communicating Artery Syndrome and other stroke syndromes. Indications may also include prophylaxis against memory impairment consecutive to ischemia or hypoxia, reduced blood flow or blood volume (including heart bypass surgery or diseases involving reduced or impaired cardiac output) or exposure to low oxygen conditions. Any therapeutic indication with clinical manifestations of cognitive dysfunction, expressed as deficits in any form or stage of attention, learning or memory linked to medical conditions in young, adult and elderly people.
  • a further aspect of the invention is a pharmaceutical composition containing at least one compound according to formula (I) and a pharmaceutically acceptable carrier material.
  • Another aspect of the present invention is a method for the treatment or prophylaxis of diseases, which are related to the orexin receptors such as eating disorders or sleep disorders comprising the administration to a patient a therapeutically effective amount of a compound of formula (I).
  • the compounds of general formula (I) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral or parental administration.
  • the compounds of general formula (I) are useful for the treatment and/or prevention of the diseases mentioned herein.
  • the invention relates to a method for the treatment and/or prevention of the diseases mentioned herein, said method comprising administering to a subject a pharmaceutically active amount of a compound of general formula (I).
  • the compounds according to general formula (I) are useful in the preparation of a medicament for the prevention or treatment of diseases selected from the group consisting of dysthymic disorders including major depression and cyclothymia, affective neurosis, all types of manic depressive disorders, delirium, psychotic disorders, schizophrenia, catatonic schizophrenia, delusional paranoia, adjustment disorders and all clusters of personality disorders; schizoaffective disorders; anxiety disorders including generalized anxiety, obsessive compulsive disorder, posttraumatic stress disorder, panic attacks, all types of phobic anxiety and avoidance; separation anxiety; all psychoactive substance use, abuse, seeking and reinstatement; all types of psychological or physical addictions, dissociative disorders including multiple personality syndromes and psychogenic amnesias; sexual and reproductive dysfunction; psychosexual dysfunction and addiction; tolerance to narcotics or withdrawal from narcotics; increased anaesthetic risk, anaesthetic responsiveness; hypothalamic-adrenal ; disturbed biological and circadian rhythms; sleep disturbances associated with diseases such
  • Compounds of general formula (I) are particularly suitable for use in the treatment of diseases or disorders selected from the group consisting of all types of sleep disorders, of stress-related syndromes, of psychoactive substance use and abuse, of cognitive dysfunctions in the healthy population and in psychiatric and neurologic disorders, of eating or drinking disorders.
  • Eating disorders may be defined as comprising metabolic dysfunction; dysregulated appetite control; compulsive obesities; emeto-bulimia or anorexia nervosa.
  • Pathologically modified food intake may result from disturbed appetite (attraction or aversion for food); altered energy balance (intake vs.
  • Drinking disorders include polydipsias in psychiatric disorders and all other types of excessive fluid intake.
  • Sleep disorders include all types of parasomnias, insomnias, narcolepsy and other disorders of excessive sleepiness, sleep-related dystonias; restless leg syndrome; sleep apneas; jet- lag syndrome; shift- work syndrome, delayed or advanced sleep phase syndrome or insomnias related to psychiatric disorders.
  • Insomnias are defined as comprising sleep disorders associated with aging; intermittent treatment of chronic insomnia; situational transient insomnia (new environment, noise) or short-term insomnia due to stress; grief; pain or illness. Insomnia also include stress-related syndromes including post-traumatic stress disorders as well as other types and subtypes of anxiety disorders such as generalized anxiety, obsessive compulsive disorder, panic attacks and all types of phobic anxiety and avoidance; psychoactive substance use, abuse, seeking and reinstatement are defined as all types of psychological or physical addictions and their related tolerance and dependence components.
  • Cognitive dysfunctions include deficits in all types of attention, learning and memory functions occurring transiently or chronically in the normal, healthy, young, adult or aging population, and also occurring transiently or chronically in psychiatric, neurologic, cardiovascular and immune disorders.
  • compounds of general formula (I) are particularly suitable for use in the treatment of diseases or disorders selected from the group consisting of sleep disorders that comprises all types of insomnias, narcolepsy and other disorders of excessive sleepiness, sleep-related dystonias, restless leg syndrome, sleep apneas, ome, shift-work syndrome, delayed or advanced sleep phase syndrome or insomnias related to psychiatric disorders.
  • compounds of general formula (I) are particularly suitable for use in the treatment of diseases or disorders selected from the group consisting of cognitive dysfunctions that comprise deficits in all types of attention, learning and memory functions occurring transiently or chronically in the normal, healthy, young, adult or aging population, and also occurring transiently or chronically in psychiatric, neurologic, cardiovascular and immune disorders.
  • compounds of general formula (I) are particularly suitable for use in the treatment of diseases or disorders selected from the group consisting of eating disorders that comprise metabolic dysfunction; dysregulated appetite control; compulsive obesities; emeto-bulimia or anorexia nervosa.
  • compounds of general formula (I) are particularly suitable for use in the treatment of diseases or disorders selected from the group consisting of psychoactive substance use and abuse that comprise all types of psychological or physical addictions and their related tolerance and dependence components.
  • the present invention also concerns a process for the preparation of a pharmaceutical composition comprising a compound of general formula (I) by mixing one or more active ingredients according to formula (I) with a carrier material in a manner known per se.
  • the compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicament (e.g. in the form of pharmaceutical preparations).
  • the pharmaceutical preparations can be administered enterally, such as orally (e.g.
  • the administration can also be effected parenterally, such as intramuscularly or intravenously (e.g. in the form of injection solutions), or topically (e.g. in the form of ointments, creams or oils).
  • compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Mark Gibson, Editor, Pharmaceutical Preformulation and Formulation, IHS Health Group, Englewood, CO, USA, 2001; Remington, The Science and Practice of Pharmacy, 20th Edition, Philadelphia College of Pharmacy and Science) by bringing the described compounds of Formula (I) and their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into dministration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
  • a further aspect of the invention is a process for the preparation of compounds of formula (I).
  • the resulting sulfonamide intermediates are transformed to compounds of formula (I) by either alkylation with tert-hvXy ⁇ bromoacetate ester, cleavage under acidic conditions followed by amidation formation with the respective R 3 -NH-CH 2 -R 4 in the presence of a coupling agent such as PyBOP (scheme 1).
  • a coupling agent such as PyBOP (scheme 1).
  • Starting compound A-NO 2 may be synthesized according to the experimental section, according to the cited references, or is commercially available.
  • the secondary amines of formula R 3 -NH-CH 2 -R 4 may be prepared either by reductive amination with the corresponding aldehyde (method A in scheme 2) or by alkylation with the corresponding halide (method B in scheme X).
  • R 4 — CHO R 4 ⁇ X X Cl, Br
  • R 4 -CH0, R 4 CH 2 X and/or R 3 -NH 2 may be synthesized according to the experimental section, according to the cited references, or is commercially available.
  • the compounds of formula (I) wherein R 3 represents ethyl and R 4 represents methyl may be prepared by reaction of the sulfonamide intermediate with 2-chloro-N,N-diethyl acetamide under basic reaction conditions (scheme 3).
  • nds of formula (I) wherein B represents S may be prepared by reaction of the corresponding acetamide with phosphorus pentasulf ⁇ de (scheme 4).
  • FCS Foatal calf serum
  • reaction mixture was poured into ice-water, basified with NaOH IM until pH 5-7,and filtered over celite. The filtrate was extracted several times with EA. The combined organic extracts were washed with brine, dried (MgSO 4 ), filtered and concentrated to yield the title compound as an oil (1.72 g, 100%).
  • reaction mixture was diluted with EA, washed with water, brine, dried (MgSO 4 ), filtered and concentrated to yield a crude orange oil.
  • the title compound was prepared according to the general procedure used for the preparation of 4-(chloro-3-nitro-phenyl)-dimethyl-amine using 4-fluoro-2-nitroaniline in place of 4- chloro-2-nitroaniline.
  • the title compound was prepared according to the general procedure used for the preparation of 4-chloro-jV', ⁇ f'-dimethyl-benzene-l,3-diamine.
  • the title compound was prepared according to the general procedure used for the preparation of 4-chloro-jV', ⁇ T-dimethyl-benzene- 1,3 -diamine.
  • the title compound was prepared according to the general procedure used for the preparation of [(2-chloro-5-dimethylamino-phenyl)-(3,4-dimethoxy-benzenesulfonyl)-amino] -acetic acid tert-butylester.
  • Example 5 2-[(3,4-dimethoxy-benzenesulfonyl)-(5-dimethylamino-2-fluoro-phenyl)-amino]-N- ethyl-N-(6-methyl-pyridin-2-ylmethyl)-acetamide prepared by reaction of [(2-fluoro-5-dimethylamino-phenyl)-(3,4-dimethoxy- benzenesulfonyl)-amino] -acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)- amine.
  • FC (EA) gave the title compound as a foam.
  • Example 7 2- [(2-Chloro-5 -dimethylamino-pheny l)-(3 ,4-dimethoxy-benzenesulfonyl)-amino] -N- ethyl-N-(6-methyl-pyrazin-2-ylmethyl)-acetamide prepared by reaction of [(2-chloro-5-dimethylamino-phenyl)-(3,4-dimethoxy- benzenesulfonyl)-amino] -acetic acid with ethyl-(6-methyl-pyrazin-2-ylmethyl)- amine.
  • FC (EA) gave the title compound as a foam.
  • LC-MS: rt 0.94 min, 563 (M + 1, ES+).
  • reaction mixture was stirred at 80 0 C under nitrogen for 3h. After cooling to RT, the reaction mixture was concentrated under reduced pressure and the residue was purified by FC (EA/ n-heptane: 8/2 to EA) to give 12 mg (57%) of the title compound as a foam.
  • Example 17 2- [(2-Chloro-5 -dimethylamino-pheny l)-(3,4-dimethoxy-benzenesulfonyl)-amino] -N- cyclopropyl-N-pyridin-2-ylmethyl-acetamide prepared by reaction of [(2-chloro-5-dimethylamino-phenyl)-(3,4-dimethoxy- benzenesulfonyl)-amino] -acetic acid with. commercially available cyclopropyl-pyridin-2- ine.
  • Example 21 2-[(6-Chloro-3-methyl-benzo[(i]isothiazol-5-yl)-(3,4-dimethoxy-benzenesulfonyl)- amino]-N-ethyl-N-(6-methyl-pyridin-2-ylmethyl)-acetamide prepared by reaction of [(6-chloro-3-methyl-benzo[d]isothiazol-5-yl)-(3,4-dimethoxy- benzenesulfonyl)-amino] -acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine. IeOH: 99/1 to 93/7) gave the title compound as a foam.
  • LC-MS: rt 0.83 min, 589 (M + 1, ES+).
  • Example 22 2-[(6-Chloro-3-methyl-benzo[(i]isothiazol-5-yl)-(3,4-dimethoxy-benzenesulfonyl)- amino]- ⁇ /-ethyl- ⁇ /-(3-methyl-pyridin-2-ylmethyl)-acetamide prepared by reaction of [(6-chloro-3-methyl-benzo[d]isothiazol-5-yl)-(3,4-dimethoxy- benzenesulfonyl)-amino] -acetic acid with ethyl-(3-methyl-pyridin-2-ylmethyl)-amine.
  • FC DCM/ MeOH: 99/1 to 93/7 gave the title compound as a foam.
  • LC-MS: rt 0.86 min, 589 (M + 1, ES+).
  • Example 26 2-[(6-Chloro-3-methyl-benzo[(i]isothiazol-5-yl)-(3,4-dimethoxy-benzenesulfonyl)-amino]-N- ethyl-JV-(l ,5-dimethyl- lH-pyrazol-3-ylmethyl)-acetamide prepared by reaction of [(6-chloro-3-methyl-benzo[d]isothiazol-5-yl)-(3,4-dimethoxy- benzenesulfonyl)-amino] -acetic acid with ethyl-(l,5-dimethyl-lH-pyrazol-3-ylmethyl)- amine.
  • FC DCM/ MeOH: 99/1 to 93/7) gave the title compound as a foam.
  • LC-MS: rt 0.98 min, 592 (M, ES+).
  • Example 29 2-[(2-Chloro-5-dimethylamino-phenyl)-(3,4-dimethoxy-benzenesulfonyl)-amino]- ⁇ /- ethyl-JV-pyrazin-2-ylmethyl-acetamide prepared by reaction of [(2-chloro-5-dimethylamino-phenyl)-(3,4-dimethoxy- benzenesulfonyl)-amino] -acetic acid with ethyl-pyrazin-2-ylmethylamine. e the title compound as a foam.
  • LC-MS: rt 0.81 min, 548 (M, ES+).
  • Example 30 [(2-Chloro-5 -dimethylamino-phenyl)-(3 ,4-dimethoxy-benzenesulfonyl)-amino] -N- ethyl-N-pyrimidin-5-ylmethyl-acetamide prepared by reaction of [(2-chloro-5-dimethylamino-phenyl)-(3,4-dimethoxy- benzenesulfonyl)-amino] -acetic acid with ethyl-pyrimidin-5-ylmethyl-amine FC (EA) gave the title compound as a foam.
  • LC-MS: rt 0.87 min, 548 (M, ES+).
  • Example 36 2- [(2-Chloro-5 -dimethylamino-pheny l)-(3,4-dimethoxy-benzenesulfonyl)-amino] -N- ethyl-N-thiazol-5-ylmethyl-acetamide prepared by reaction of [(2-chloro-5-dimethylamino-phenyl)-(3,4-dimethoxy- benzenesulfonyl)-amino] -acetic acid with ethyl-thiazol-5-ylmethyl-amine
  • Example 44 2-[(2-Chloro-5-dimethylamino-phenyl)-(3,4-dimethoxy-benzenesulfonyl)-amino]-N- ethyl-(5 -methyl-pyridin-3 -ylmethyl)-acetamide prepared by reaction of [(2-chloro-5-dimethylamino-phenyl)-(3,4-dimethoxy- benzenesulfonyl)-amino] -acetic acid with ethyl-(5 -methyl-pyridin-3 -ylmethyl)-amine
  • Example 51 2- [(2-Chloro-5 -dimethylamino-phenyl)-(3 ,4-dimethoxy-benzenesulfonyl)-amino] -N- ethyl-N-isothiazol-5-ylmethyl-acetamide prepared by reaction of [(2-chloro-5-dimethylamino-phenyl)-(3,4-dimethoxy- benzenesulfonyl)-amino] -acetic acid with ethyl-isothiazol-5-ylmethyl-amine
  • Example 59 2- [(2-Chloro-5 -dimethylamino-phenyl)-(3 ,4-dimethoxy-benzenesulfonyl)-amino] -N- ethyl-N-(6-methoxy-pyridin-2-ylmethyl)-acetamide prepared by reaction of N-(2-chloro-5-dimethylamino-phenyl)-3,4-dimethoxy- benzenesulfonamide with ethyl-(6-methoxy-pyridin-2-ylmethyl)-amine
  • the orexin receptor antagonistic activity of the compounds of formula (I) is determined in accordance with the following experimental method.
  • CHO cells expressing the human orexin- 1 receptor and the human orexin-2 receptor, respectively, are grown in culture medium (Ham F- 12 with L-Glutamine) containing 300 ⁇ g/ml G418, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin and 10 % inactivated fetal calf serum (FCS).
  • FCS fetal calf serum
  • the cells are seeded at 80O00 cells / well into 96-well black clear bottom sterile plates (Costar) which have been precoated with 1% gelatine in Hanks' Balanced Salt Solution (HBSS). All reagents are from Gibco BRL. The seeded plates are incubated overnight at 37°C in 5% CO 2 .
  • Human orexin-A as an agonist is prepared as 1 mM stock solution in methanol: water (1 :1), diluted in HBSS containing 0.1 % bovine serum albumin (BSA) and 2 mM HEPES for use in the assay at a final concentration of 10 nM.
  • BSA bovine serum albumin
  • Antagonists are prepared as 10 mM stock solution in DMSO, then diluted in 96-well plates, first in DMSO, then in HBSS containing 0.1 % bovine serum albumin (BSA) and 2 mM HEPES.
  • BSA bovine serum albumin
  • the 96-well plates are incubated for 60 min at 37° C in 5% CO 2 .
  • the loading solution is then aspirated and cells are washed 3 times with 200 ⁇ l HBSS containing 2.5 mM probenecid, 0.1% BSA, 2 mM HEPES. 100 ⁇ l of that same buffer is left in each well.
  • antagonists are added to the plate in a volume of 50 ⁇ l, incubated for 20 min and finally 100 ⁇ l of agonist is escence is measured for each well at 1 second intervals, and the height of each fluorescence peak is compared to the height of the fluorescence peak induced by 10 nM orexin-A with buffer in place of antagonist.
  • IC 50 value the concentration of compound needed to inhibit 50 % of the agonistic response
  • Antagonistic activities of compounds are in the nanomolar range with respect to OXi and OX 2 receptors. Selected compounds are displayed in Table 1.

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Abstract

L'invention concerne de nouveaux composés sulfonamides correspondant à la formule (I) dans laquelle A, B, R3 et R4 sont définis dans les revendications et leur utilisation en tant qu'antagonistes des récepteurs de l'orexine, utilisés dans la prévention et le traitement de troubles de l'alimentation et d'absorption de liquides, de tous types de troubles du sommeil, des dysfonctionnements cognitifs en tous genres dans une population en bonne santé et de troubles psychiatriques ou neurologiques.
EP07735447A 2006-04-11 2007-04-10 Nouveaux composés sulfonamides Withdrawn EP2007717A1 (fr)

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US8242121B2 (en) 2007-05-23 2012-08-14 Merck Sharp & Dohme Corp. Pyridyl piperidine orexin receptor antagonists
EP2025674A1 (fr) 2007-08-15 2009-02-18 sanofi-aventis Tetrahydronaphthaline substituée, son procédé de fabrication et son utilisation en tant que médicament
ES2364806T3 (es) * 2008-01-21 2011-09-14 F. Hoffmann-La Roche Ag Sulfonamidas como antagonistas de orexina.
FR2962649A1 (fr) 2010-07-19 2012-01-20 Conservatoire Nat Arts Et Metiers Traitement d'une pathologie liee a un effet excessif du tnf par un compose de benzene sulfonamide
US8828995B2 (en) 2011-03-08 2014-09-09 Sanofi Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
US8828994B2 (en) 2011-03-08 2014-09-09 Sanofi Di- and tri-substituted oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
US8871758B2 (en) 2011-03-08 2014-10-28 Sanofi Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
AR088352A1 (es) 2011-10-19 2014-05-28 Merck Sharp & Dohme Antagonistas del receptor de 2-piridiloxi-4-nitrilo orexina
US9440982B2 (en) 2012-02-07 2016-09-13 Eolas Therapeutics, Inc. Substituted prolines/piperidines as orexin receptor antagonists
WO2013119639A1 (fr) 2012-02-07 2013-08-15 Eolas Therapeutics, Inc. Pipéridines/prolines substituées en tant qu'antagonistes du récepteur de l'orexine
US9682085B2 (en) 2013-02-22 2017-06-20 Shifa Biomedical Corporation Anti-proprotein convertase subtilisin kexin type 9 (anti-PCSK9) compounds and methods of using the same in the treatment and/or prevention of cardiovascular diseases
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CN105473141A (zh) 2013-03-15 2016-04-06 实发生物医学公司 治疗和/或预防心血管疾病的抗pcsk9化合物和方法
SG11201604639YA (en) * 2013-12-12 2016-07-28 Univ Tsukuba Sulfonamide derivative or pharmaceutically acceptable acid addition salt thereof
JP6663909B2 (ja) 2014-08-13 2020-03-13 エオラス セラピューティクス， インコーポレイテッド オレキシンレセプターモジュレーターとしてのジフルオロピロリジン
WO2016199906A1 (fr) * 2015-06-12 2016-12-15 国立大学法人筑波大学 Dérivé de sulfonamide et sel d'addition d'acide pharmaceutiquement acceptable de celui-ci
EP3414241B1 (fr) 2016-02-12 2022-05-04 Astrazeneca AB Pipéridines halosubstituées en tant que modulateurs de récepteur des orexines
AU2017281003B2 (en) 2016-06-21 2020-11-26 Shifa Biomedical Corporation Anti-proprotein convertase subtilisin kexin type 9 (anti-PCSK9) compounds and methods of using the same in the treatment and/or prevention of cardiovascular diseases
CN112409342B (zh) * 2019-08-23 2022-12-13 南京理工大学 基于糠醛的有机光致变色材料及其制备方法

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